All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
Delta-9 tetrahydrocannabinol (Δ9-THC) and (−)-cannabidiol (CBD) are the two major constituents of the Cannabis sativa (marihuana) plant. Δ9-THC is psychoactive and binds to cannabinoid CB1 receptors located in the brain and the periphery [Herkenham, M. (1995) Cannabinoid receptors, London, Academic Press: 145-166; Pertwee, R. G. (1997) Pharmacol. Ther. 74, 129], as well as to CB2 receptors which are located exclusively on non-neural tissue, such as immune cells [Pertwee (1997) id. ibid.]. CBD binds neither receptor and is not psychoactive. Δ9-THC is considered to be responsible for virtually all central effects observed with the cannabis plant and for many of its peripheral effects [Pertwee (1997) id. ibid.; Mechoulam, R. et al. (1998) Prog. Med. Chem. 35, 199; Fride, E. and C. Sanudo-Pena (2002) Cannabinoids and endocannabinoids: behavioral and developmental aspects. In: The Biology of Marijuana, ed. E. Onaivi, Harwood Academic Publishers, Reading]. Peripheral effects include inhibition of gastrointestinal activity [Pinto, L. (2002) Prostaglandins Leukot Essent Fatty Acids 66, 333] and anti-inflammatory effects [Mechoulam (1998) id. ibid.].
In view of the abundance of CB1 and CB2 receptors on immune cells [Galiegue, S. et al. (1995) Eur. J. Biochem. 232(1): 54-61; Pertwee (1997) id. ibid.], it is not surprising that cannabinoids are effective regulators of the inflammatory process including peripheral pain [Hanus, L. et al. (1999) Proc. Natl. Acad. Sci. USA 96, 14228; Mechoulam (1998) id. ibid.; Malfait, A. M. et al. (2000) Proc. Natl. Acad. Sci. USA 97, 9561].
There is ample evidence in vitro and in vivo for an inhibitory action of Δ9-THC and other cannabinoids and endocannabinoids (anandamide, 2-arachidonoyl glycerol, 2-AG and noladine ether, see [Fride, E. (2002) Endocannabinoids in the central nervous system—an overview. Prostaglandins, Leukotrienes and Essential Fatty Acids.] on intestinal motility in various species such as mice, rats and guinea pigs [Pertwee (1997) id. ibid; Pinto (2002) id. ibid.]. Early work includes in vivo evidence for an inhibitory effect of Δ9-THC on intestinal motility in mice [Chesher, G. B. et al. (1973) Br. J. Pharmacol. 49(4): 588-94]. Endocannabinoid-induced inhibition of intestinal motility was first demonstrated for anandamide as a near cessation of defecation in mice [Fride, E. and R. Mechoulam (1993) Eur. J. Pharmacol. 231, 313; Fride, E. (1995) Brain Res. 697, 83].
Most evidence suggest that the cannabinoid-induced gastrointestinal inhibition is mediated by CB1 receptors [Colombo, G. et al. (1998) Eur. J. Pharmacol. 344(1): 67-9; Pertwee, R. G. (2001) Gut 48(6): 859-67, Pinto, L. (2002) Prostaglandins Leukot Essent Fatty Acids 66, 333; Calignano, A. et al. (1973) Br J Pharmacol 49, 588]. This is in agreement with a presence of CB1 receptors and CB1 receptor mRNA [Casu, M. A. et al. (2003) Eur. J. Pharmacol. 459(1): 97-105; Griffin, G. et al. (1997) Eur. J. Pharmacol. 339, 53], but not of CB2 receptor mRNA in the mesenteric plexus of the gut. It has also been determined that gastrointestinal transit is regulated locally in the periphery rather than by centrally located CB1 receptors [Izzo, A. et al. (2000) Br. J. Pharmacol. 129(8): 1627-32; Landi, M. et al. (2002) Eur. J. Pharmacol. 450, 77].
On the other hand, the inventors have shown previously that the selective CB2 receptor agonist, HU-308, inhibited defecation which was antagonized by the selective CB2 receptor antagonist SR144528, but not by the CB1 receptor antagonist SR141716A [Hanus (1999) id. ibid.].
These findings suggest that cannabinoids may be developed as therapeutic agents in conditions such as inflammatory pain and inflammatory bowel diseases. The significant drawback for the use of cannabis or Δ9-THC is the unwanted psychoactive side effects, such as anxiety, confusion and memory impairment, which may be observed with higher doses [Robson, P. (2001) Br. J. Psychiatry 178, 107]. Therefore current efforts are aimed at developing cannabinoids with medical benefits but which are devoid of psychoactive side effects.
Despite the dichotomy between Δ9-THC and CBD, CBD displays a number of pharmacological activities, which are similar to those of Δ9-THC. These include anti-emetic [Parker, L. A. et al. (2002) Neuroreport 13, 567] and anti-inflammatory effects [Malfait, A. M. et al. (2000) Proc. Natl. Acad. Sci. USA 97, 9561]. Being devoid of psychoactive effects, CBD is a good candidate for future development of peripherally acting cannabinoid-like drugs.
The present inventors have previously described several (−)-CBD derivatives and their activity as anti-inflammatory agents, analgesics, neuroprotective and antipsychotic as well as anti-cancer agents [WO 01/95899]. This publication also describes the synthesis of the (−)-(CBD) derivatives. Other derivatives, which contain etheric groups, were described in the review of Johnson and Melvin [Johnson, M. R. and Melvin, L. S. (1986) The discovery of non-classical cannabinoids analgetics. In: Cannabinoids as therapeutic agents. Ed. R. Mechoulam, CRS Press Fl., pp. 121-145].
In a previous report [Bisogno et al. (2001) id ibid], the inventors described the biochemical properties of a number of derivatives of the natural (−)-CBD as well as the synthetic (+)-CBD, namely (+)-CBD-DMH and (+)-7-OH-CBD-DMH. Only the latter (+) analogues were found to bind CB1 and/or CB2 receptors. Vannilloid VR1 receptors or increased levels of the endocannabinoid anandamide may mediate effects of some, but not all analogues. Based on such findings, candidates for anti-inflammatory or other therapeutic activity may be developed.
In search for selective agonists/antagonists of the peripheral cannabinoid system, which would not affect the central nervous system, which are an object of the present invention, the inventors examined the aforementioned (+)-CBD, (+)-CBD-DMH and (+)-7-OH-CBD-DMH, and several novel (+)CBD analogues, particularly (+)-7-OH-CBD, (+)-COOH-CBD and (+)-COOH-CBD-DMH), for central as well as peripheral activity in mice. Some synthetic (+)-CBD derivatives were indeed found to possess such selective activity.
It is therefore an object of the present invention to provide (+)-CBD derivatives for use as selective modulators of the peripheral nervous system. Further objects of the present invention are to provide (+)-CBD derivatives for use as analgesics, anti-inflammatory and anti-diarrheal agents.
It is a further object of the present invention to provide novel (+)-CBD derivatives, which may be useful as selective modulators of the peripheral nervous system.
These and other objects of the invention will become apparent as the description proceeds.